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PubMed2005

Evaluation of rage isoforms, ligands, and signaling in the brain.

Since the identification of the receptor for advanced glycosylation end products (RAGE) in 1992, there have been tremendous strides made in our understanding of the role RAGE receptors play in a variety of physiological and pathological processes. Despite such progress, several fundamental aspects of RAGE expression and RAGE function remain largely unanswered. In particular, while multiple forms of the RAGE receptor are known to exist, little is known with regards to how these different isoforms of the RAGE receptor work together to mediate RAGE signaling. For example, some forms of the RAGE receptor may promote deleterious feed-forward pathways, while others may serve to inhibit deleterious activation of the RAGE receptor. Additionally, important questions remain with regards to the intracellular domain of the full-length RAGE receptor, and the specifics surrounding how intracellular signaling pathways become activated via the RAGE family of receptors. The focus of this review is to address each of these important issues, as well as other key aspects of RAGE biology, and discuss how they are important for both our understanding of the physiological and pathological roles of RAGE signaling within the brain.

Animals↗
PubMed2003

The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment.

The pattern recognition receptor, RAGE (receptor for advanced glycation endproducts), propagates cellular dysfunction in several inflammatory disorders and diabetes. Here we show that RAGE functions as an endothelial adhesion receptor promoting leukocyte recruitment. In an animal model of thioglycollate-induced acute peritonitis, leukocyte recruitment was significantly impaired in RAGE-deficient mice as opposed to wild-type mice. In diabetic wild-type mice we observed enhanced leukocyte recruitment to the inflamed peritoneum as compared with nondiabetic wild-type mice; this phenomenon was attributed to RAGE as it was abrogated in the presence of soluble RAGE and was absent in diabetic RAGE-deficient mice. In vitro, RAGE-dependent leukocyte adhesion to endothelial cells was mediated by a direct interaction of RAGE with the beta2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with beta1-integrins. The RAGE-Mac-1 interaction was augmented by the proinflammatory RAGE-ligand, S100-protein. These results were corroborated by analysis of cells transfected with different heterodimeric beta2-integrins, by using RAGE-transfected cells, and by using purified proteins. The RAGE-Mac-1 interaction defines a novel pathway of leukocyte recruitment relevant in inflammatory disorders associated with increased RAGE expression, such as in diabetes, and could provide the basis for the development of novel therapeutic applications.

Animals↗
PubMed1997

Advanced glycation end product (AGE)-mediated induction of tissue factor in cultured endothelial cells is dependent on RAGE.

BACKGROUND: Binding of advanced glycation end products (AGEs) to the cellular surface receptor (RAGE) induces translocation of the transcription factor NF-kappaB into the nucleus and NF-kappaB-mediated gene expression. This study examines the role of RAGE in the AGE albumin-mediated induction of endothelial tissue factor, known to be partly controlled by NF-kappaB. METHODS AND RESULTS: Endothelial cells (ECs) were incubated in the presence of an 18-mer phosphorothioate oligodeoxynucleotide antisense to the 5'-coding sequence of the RAGE gene (antisense RAGE; 0.1 micromol/L). Sense oligonucleotides (sense RAGE, 0.1 micromol/L) of the same region served as control. The cellular uptake of oligonucleotides was controlled by immunofluorescence microscopy. RAGE transcription was suppressed by antisense RAGE, as demonstrated by RT-PCR reactions. AGE albumin-mediated activation of cultured ECs was studied after 48 hours of preincubation of ECs with antisense or sense RAGE. Electrophoretic mobility shift assays and Western blot analysis demonstrated that the AGE albumin-induced translocation of NF-kappaB from the cytoplasm into the nucleus was suppressed in the presence of antisense RAGE but not by sense RAGE. In parallel, AGE albumin-mediated tissue factor transcription, activity, and antigen were significantly reduced in ECs exposed to antisense RAGE, whereas sense RAGE (and nonspecific oligonucleotides) did not influence tissue factor expression. CONCLUSIONS: Activation of ECs and induction of tissue factor by AGE albumin in ECs is dependent on RAGE.

Animals↗
PubMedDate not supplied

Assessing road rage victimization and perpetration in the Ontario adult population: the impact of illicit drug use and psychiatric distress.

BACKGROUND: To investigate the association among illicit drug use, psychiatric distress and road rage victimization and offending. Particular attention is given to the most serious forms of road rage behaviour. METHODS: The data are based on the 2002 CAMH Monitor and include a sample of 2,421 Ontario adults aged 18 and older. Logistic regression analyses were conducted with illicit drug use and psychiatric distress (GHQ) and demographic factors as independent variables. RESULTS: Past-year road rage victimization was reported by 42% of the sample and 31% reported any type of road rage offending. Approximately 5% were classified as respondents with serious road rage involvement. The logistic regression analyses revealed significant relationships between illicit drug use and road rage outcomes. Cannabis use was significantly associated with general road rage victimization and offending, while stimulant use substantially increased the likelihood of victimization and membership in the serious road rage classification. Psychiatric distress significantly increased the odds of both road rage victimization and serious road rage involvement. CONCLUSION: These data reveal different indicators of road rage offending, victimization and serious involvement. Further work is needed to clarify the mechanisms associated with the relationship among stimulant use, psychiatric distress and serious road rage involvement.

Adolescent↗
PubMed2004

Down-regulation of the receptor for advanced glycation end-products (RAGE) supports non-small cell lung carcinoma.

The receptor for advanced glycation end-products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily. Several ligands binding to RAGE have been identified, including amphoterin. Experimental studies have given rise to the discussion that RAGE and its interaction with amphoterin contribute to tumour growth and metastasis. However, none of the studies considered a differential transcription profile in cancer that might change the interpretation of the study results when comparing RAGE in tumours with histologically normal tissues. Here we show that RAGE is strongly reduced at the mRNA and even more so at the protein level in non-small cell lung carcinomas compared with normal lung tissues. Down-regulation of RAGE correlates with higher tumour (TNM) stages but does not depend on the histological subtypes, squamous cell lung carcinoma and adenocarcinoma. Subsequent overexpression of full-length human RAGE in lung cancer cells (NCI-H358) showed diminished tumour growth under some conditions. While proliferation of RAGE-expressing cells was less than that of cells expressing the cytoplasmic domain deletion mutant DeltacytoRAGE or mock-transfected NCI-H358 in monolayer cultures, RAGE cells also formed smaller tumours in spheroid cultures and in vivo in athymic mice compared with DeltacytoRAGE cells. Moreover, we observed a more epithelial growth of RAGE-expressing, but also of DeltacytoRAGE-expressing, cells on collagen layers, whereas mock NCI-H358 cells kept their tumour morphology. This observation was supported by immunofluorescence analyses demonstrating that RAGE preferentially localizes at intercellular contact sites, independent of expression of the cytoplasmic domain. Thus, down-regulation of RAGE may be considered as a critical step in tissue reorganization and the formation of lung tumours.

Animals↗
PubMed1998

RAGE-Abeta interactions in the pathophysiology of Alzheimer's disease.

RAGE is a cell surface molecule primarily identified for its capacity to bind advanced glycation end-products and amphoterin. Immunocytochemical studies demonstrated that in Alzheimer's Disease (AD) the expression of RAGE is elevated in neurons close to neuritic plaque beta-amyloid (Abeta) deposits and in the cells of Abeta containing vessels. Cross-linking of surface bound Abeta 1-40 to endothelial cells, yielded a band of 50 kDa identified as RAGE. Using the soluble extracellular domain of recombinant human RAGE, we found that Abeta binds to RAGE with a Kd = 57 +/- 14 nM, a value close to those found for mouse brain endothelial cells and rat cortical neurons. The interaction of Abeta with RAGE in neuronal, endothelial, and RAGE-transfected COS-1 cells induced oxidative stress, as assessed by the TBARS and MTT assays. ELISA demonstrated a 2.5 times increase of RAGE in AD over control brains. Activated microglia also showed elevated expression of RAGE. In the BV-2 microglial cell line, RAGE bound Abeta in dose dependent manner with a Kd of 25 +/- 9 nM. Soluble Abeta induced the migration of microglia along a concentration gradient, while immobilized Abeta arrested this migration. Abeta-RAGE interaction also activated NF-kappaB, resulting in neuronal up-regulation of macrophage-colony stimulating factor (M-CSF) which also induced microglial migration. Taken together, our data suggest that RAGE-Abeta interactions play an important role in the pathophysiology of Alzheimer's Disease.

Journal Article↗
PubMedDate not supplied

Causes and consequences of air rage in Canada: cases in newspapers.

OBJECTIVES: To outline the causes and consequences of air rage, describe victims and perpetrators, suggest hypotheses for further study and compare road rage to air rage cases. METHOD: We analyzed 29 air rage cases reported in the Canadian Press for the time period 1998 to 2000. RESULTS: It was found that excessive alcohol use and tobacco smoking were the most important precipitating factors. Physical aggression was common in air rage but serious injuries were not. The psychological stress of air rage for passengers must be considerable but it has not been assessed. Air rage and road rage are predominantly attributable to young males. However, alcohol and tobacco use are not important factors in road rage. DISCUSSION: Preventing air rage will be difficult and will depend on better training for airline staff. More research is needed on air rage, especially the role of mental illness and prescription drug use. Prospective studies of air rage cases are needed.

Aggression↗
PubMed2003

The "homogamy" of road rage: understanding the relationship between victimization and offending among aggressive and violent motorists.

The issue of "road rage" has received increasing media and scholarly attention in recent years. Using a representative sample of 2610 adults from Ontario, involvement with road rage was surveyed across demographic subgroups. Incidents of road rage were divided into two categories, verbal-gesturing road rage and physical-threats road rage. Drawing upon violence and criminological literature, experiences of road rage victimization and offending were explored, as well as the extent to which individuals were simultaneously the victims and perpetrators of road rage. Results challenge findings from the violence literature that males and young adults have the greatest propensity for violent victimization. Road rage offending was predominantly a male activity, while there were no gender differences in victimization. Moreover, road rage was not isolated among young adults; rather, road rage was prominent across all ages, with the exception of seniors. Consistent with the existing literature, road rage was higher in urban settings.

Adolescent↗
PubMed2003

RAGE is expressed in pyramidal cells of the hippocampus following moderate hypoxic-ischemic brain injury in rats.

The receptor for advanced glycation end products (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. The RAGE-ligand interaction has a putative role in a range of chronic disorders and is also known to contribute to both inflammatory/degenerative processes as well as regeneration in peripheral nerve injury. We have investigated the expression of RAGE in the moderate hypoxic-ischemic (HI) rat brain injury model in order to determine if this receptor is involved in the cellular perturbation mediated by ischemic stress. RAGE mRNA levels were detected by in situ hybridization using a DIG-labelled 48 mer oligonucleotide probe. Results showed a high level of expression of RAGE mRNA in the CA1/2 pyramidal cell layer of the hippocampus on the lesioned side of the brain 72 h after a moderate hypoxic-ischemic insult. RAGE was not expressed on the control side of the hippocampus. The RAGE-positive cells had a unique morphology, being angular in shape and atrophied with a condensed cell nucleus. They were NeuN-positive and were identified as dying cells by staining with thionin/acid fuchsin. A subset of cells was positive for cleaved Caspase-3, a marker for apoptosis. Together these data show that RAGE is expressed in dying neurons and suggest that RAGE may have a role in neuronal cell death mediated by ischemic stress. Identification of the ligand for RAGE in the ischemic brain may lead to a better understanding of RAGE-mediated cellular dysfunction in the CNS.

Animals↗
PubMed2003

The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site.

The receptor for advanced glycation end-products (RAGE)-mediated cellular activation through the mitogen-activated protein kinase (MAPK) cascade, activation of NF-kappaB and Rho family small G-proteins, cdc42/Rac, is implicated in the pathogenesis of inflammatory disorders and tumor growth/metastasis. However, the precise molecular mechanisms for the initiation of cell signaling by RAGE remain to be elucidated. In this study, proteins which directly bind to the cytoplasmic C-terminus of RAGE were purified from rat lung extracts using an affinity chromatography technique and identified to be extracellular signal-regulated protein kinase-1 and -2 (ERK-1/2). Their interactions were confirmed by immunoprecipitation of ERK-1/2 from RAGE-expressing HT1080 cell extracts with anti-RAGE antibody. Furthermore, the augmentation of kinase activity of RAGE-bound ERK upon the stimulation of cells with amphoterin was demonstrated by determining the phosphorylation level of myelin basic protein, an ERK substrate. In vitro binding studies using a series of C-terminal deletion mutants of human RAGE revealed the importance of the membrane-proximal cytoplasmic region of RAGE for the direct ERK-RAGE interaction. This region contained a sequence similar to the D-domain, a ERK docking site which is conserved in some ERK substrates including MAPK-interacting kinase-1/2, mitogen- and stress-activated protein kinase-1, and ribosomal S6 kinase. These data suggest that ERK may play a role in RAGE signaling through direct interaction with RAGE.

Amino Acid Sequence↗
PubMed2002

AGEs bind to mesothelial cells via RAGE and stimulate VCAM-1 expression.

BACKGROUND: Excess advanced glycation end-products (AGEs) are formed during renal failure, and AGE formation also may be connected with the high glucose concentration of peritoneal dialysis (PD) fluids. To determine the effect of human peritoneal mesothelial cell (HPMC) exposure to glycated proteins, we studied the HPMC receptor of AGE expression (RAGE), and analyzed the results of AGE-RAGE interaction on adhesion molecule expression and leukocyte binding. METHODS: RAGE was detected by FACS analysis, and RAGE mRNA by reverse transcription-polymerase chain reaction (RT-PCR). Vascular and intercellular cell adhesion molecule (VCAM-1 and ICAM-1) expression was measured by a known radiometric technique under basal conditions, after the addition of an AGE-specific compound, Nepsilon-carboxylmethyllysine (CML-albumin). Leukocyte adhesion on HPMC was analyzed by videomicroscopy after HPMC stimulation. RESULTS: RAGE protein was detected on HPMC, and RAGE mRNA was evidenced by RT-PCR. VCAM-1 expression was stimulated by CML-albumin (P < 0.01), while ICAM-1 was unchanged. By blocking the AGE-RAGE interaction, anti-RAGE antibodies or recombinant RAGE inhibited the increase in VCAM-1 expression. CML-albumin stimulation potentiated leukocyte adhesion to HPMC (P < 0.001). This effect was prevented by the incubation of leukocytes with recombinant VCAM-1 (P < 0.001). CONCLUSIONS: AGE binding to RAGE stimulated mesothelial cell activity, and resulted in the overexpression of VCAM-1, a structure for leukocyte adhesion. The AGE-RAGE interaction resulted in HPMC activation, which may promote local inflammation, and thus is implicated in the peritoneal injury found in long-term PD patients.

Adult↗
PubMed1998

Sp1-binding elements in the promoter of RAGE are essential for amphoterin-mediated gene expression in cultured neuroblastoma cells.

Receptor for AGE (RAGE) and the polypeptide amphoterin are highly expressed and co-localized in neurons of the developing central nervous system of the rat. In vitro, the interaction of amphoterin with neuronal RAGE induces neurite outgrowth. We tested the hypothesis that interaction of amphoterin with neuronal cells enhances RAGE expression, thereby providing a mechanism by which amphoterin-mediated regulation of RAGE might contribute to promotion of neurite growth and spreading. Incubation of cultured neuroblastoma cells with amphoterin resulted in increased transcription and translation of RAGE, a process largely inhibited in the presence of anti-RAGE IgG but not by nonimmune IgG. To begin to delineate molecular mechanisms underlying these findings, we identified multiple putative binding elements within the 5'-flanking region of the RAGE gene for Sp1, a transcription factor that has been critically linked to the process of normal development. DNase I footprinting and electrophoretic mobility shift assays demonstrated multiple functional Sp1-binding sites within the region -245 to -40 of the RAGE promoter. Transient transfection of cultured SK-N-SH neuroblastoma cells with chimeric 5'-deletion constructs linked to luciferase reporter revealed that the region containing Sp1-binding elements did not contribute uniquely to basal expression of the RAGE gene. Simultaneous mutation of the multiple Sp1-binding elements in this region did not affect basal promoter function; however, promoter responsiveness to amphoterin was markedly attenuated. These results point to Sp1-dependent mechanisms underlying amphoterin-mediated increases in RAGE expression in neuroblastoma cells and further link amphoterin-RAGE interaction to development of the nervous system.

Animals↗
PubMed2002

Tumor-associated antigens as possible targets for immune therapy in head and neck cancer: comparative mRNA expression analysis of RAGE and GAGE genes.

Specific immune therapy targeting residual areas of cancer cells may emerge as a powerful treatment strategy for head and neck squamous cell carcinoma (HNSCC). In order to define possible targets for immune therapy, we evaluated the frequency of two groups of tumor antigens-the RAGE and GAGE families-by means of reverse transcriptase polymerase chain reaction using primary HNSCCs (n = 28), mucosa specimens as normal controls (n = 10) and HNSCC cell lines (n = 6). By means of specific primer selection we could differentiate between RAGE-1, -2, -3 and -4, as well as between two groups of GAGE genes (GAGE-1,2,7 vs GAGE-3,4,5,6,8). While all mucosa tissues (from smokers and non-smokers) were negative for both antigen families, 24/28 investigated tumors were positive for up to 5 tumor antigens. Among the RAGE genes, RAGE-1-positive tumors were the most abundant (8/28), followed by RAGE-2 (7/28) and RAGE-4 (6/28). Differences in the locations of HNSCCs were reflected by different RAGE family members being expressed most frequently: larynx, RAGE-1; oropharynx, RAGE-2; and hypopharynx, RAGE-4. Primers against GAGE-1,2,7 and GAGE-3,4,5,6,8 revealed 6/27 and 16/27 positive tumors, respectively. This report suggests that RAGE genes and GAGE-3,4,5,6,8 may be promising candidates for specific immune therapy in HNSCC.

Antigens, Neoplasm↗
PubMed2006

The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock.

The receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of numerous conditions associated with excessive inflammation. To determine whether RAGE-dependent signaling is important in the development of intestinal barrier dysfunction after hemorrhagic shock and resuscitation (HS/R), C57Bl/6, rage(-/-), or congenic rage(+/+) mice were subjected to HS/R (mean arterial pressure of 25 mmHg for 3 h) or a sham procedure. Twenty-four hours later, bacterial translocation to mesenteric lymph nodes and ileal mucosal permeability to FITC-labeled dextran were assessed. Additionally, samples of ileum were obtained for immunofluorescence microscopy, and plasma was collected for measuring IL-6 and IL-10 levels. HS/R in C57Bl/6 mice was associated with increased bacterial translocation, ileal mucosal hyperpermeability, and high circulating levels of IL-6. All of these effects were prevented when C57Bl/6 mice were treated with recombinant human soluble RAGE (sRAGE; the extracellular ligand-binding domain of RAGE). HS/R induced bacterial translocation, ileal mucosal hyperpermeability, and high plasma IL-6 levels in rage(+/+) but not rage(-/-) mice. Circulating IL-10 levels were higher in rage(-/-) compared with rage(+/+) mice. These results suggest that activation of RAGE-dependent signaling is a key factor leading to gut mucosal barrier dysfunction after HS/R.

Animals↗
PubMed1994

Neuroanatomical and neurochemical mechanisms underlying amygdaloid control of defensive rage behavior in the cat.

1. It is well established that the hypothalamus and midbrain periaqueductal gray (PAG) play important roles in the expression of defensive rage behavior. While defensive rage is not elicited from the amygdala, this region of the limbic system nevertheless serves an important role in the modulation of defensive rage behavior. The present paper attempts to address the question of how the amygdala modulates defensive rage behavior in the cat. The studies were conducted using brain stimulation, pharmacological, neuroanatomical and immunocytochemical methods to identify the likely neural pathways and their associated neurotransmitters by which different regions of the amygdala modulate defensive rage behavior in the cat. 2. The experimental evidence provided thus far establishes that three regions of the amygdala have been identified as powerful modulators of defensive rage behavior. These include the medial nucleus, basal complex and central nucleus of the amygdala. Experiments involving dual stimulation of an amygdaloid nucleus and sites within the medial hypothalamus or PAG from which defensive rage behavior was elicited demonstrated that two of the regions facilitated defensive rage --the medial nucleus and basal complex--and a third region--the central nucleus--suppressed defensive rage. The mechanisms and substrates underlying modulation for each of these regions are different. Medial amygdaloid facilitation of defensive rage involves a pathway (i.e., the stria terminalis) that projects directly to the medial hypothalamus and utilizes substance P as a neurotransmitter. Basal amygdaloid facilitation of defensive rage behavior makes use of a pathway to the PAG in which excitatory amino acids acting on NMDA receptors are utilized as a neurotransmitter. The central nucleus also projects to the PAG. However, it is strongly inhibitory and utilizes enkephalins that act upon mu receptors within the PAG.

Aggression↗
PubMed2002

Rage 2002.

Rage is the rage today. New phrases continue to make the headlines: sky rage, road rage, school rage, workplace rage, sports rage, parent sport observer rage, prayer rage, courtroom rage and more. The Internet advertises aggressive driver course: road rageous.

Adult↗
PubMed1998

GABA receptor mediated suppression of defensive rage behavior elicited from the medial hypothalamus of the cat: role of the lateral hypothalamus.

Recently, our laboratory has demonstrated that predatory attack behavior in the cat, elicited by electrical stimulation of the lateral hypothalamus, is suppressed following activation of the region of the medial hypothalamus from which defensive rage behavior is elicited [Han, Y., Shaikh, M.B., Siegel, A., Medical amygdaloid suppression of predatory attack behavior in the cat: II. Role of a GABAergic pathway from the medial to the lateral hypothalamus, Brain Res., 716 (1996) 72-83.]. The mechanism for this suppression is a direct GABAergic projection from the medial to lateral hypothalamus. The present study tested the hypothesis that the inhibitory relationship between these two regions of hypothalamus is reciprocal, namely, that a GABAergic neuron, which also projects from the lateral to medial hypothalamus, serves to suppress defensive rage elicited from the medial hypothalamus. Monopolar stimulating electrodes were implanted into lateral hypothalamic sites from which predatory attack behavior was elicited. In addition, cannula-electrodes were implanted into the medial hypothalamus for elicitation of defensive rage behavior and for microinjections of GABA compounds. Initially, in the absence of drug administration, the effects of dual stimulation of the lateral and medial hypothalamus upon response latencies were compared with those following single stimulation of the medial hypothalamus alone. Dual stimulation significantly (p<0.01) suppressed defensive rage behavior elicited from the medial hypothalamus. Then, administration of the GABAA receptor antagonist, bicuculline (10-60 pmol), into medial hypothalamic sites from which defensive rage was elicited blocked the suppressive effects of lateral hypothalamic stimulation. The GABAA receptor agonist, muscimol (0.3-30 pmol), microinjected into the medial hypothalamus, suppressed defensive rage elicited by single stimulation of the medial hypothalamus in a dose dependent manner. These suppressive effects of muscimol upon defensive rage were blocked following pretreatment with bicuculline (60 pmol). Administration of muscimol into adjoining regions of the lateral hypothalamus had no effect upon defensive rage, indicating its site specificity. Bicuculline (60 pmol) delivery into the medial hypothalamus had no effect upon defensive rage, suggesting the, presence of a phasic rather than tonic mechanism. A combination of immunocytochemical and retro grade tracing procedures were then employed to determine the origin of the putative GABAergic pathway projecting to the medial hypothalamus. In this experiment, the retrograde tracer, Fluoro-Gold (8%, 0.5 microl), was microinjected through a cannula-electrode in the medial hypothalamus from which defensive rage had been elicited. Following survival periods of 5-6 days, cats were perfused with 4% paraformaldehyde and brain tissue was processed for immunocytochemical staining of GABA neurons. Retrogradely labeled, immunopositively labeled, as well as Fluoro-Gold and GABA labeled cells, were identified in the lateral hypothalamus. Each type of neuron was distributed over wide regions of the lateral hypothalamus, extending from the area immediately caudal to the optic chiasm to the level of the posterior hypothalamus. Together, the behavioral pharmacological and anatomical data provide evidence of a direct inhibitory projection from the lateral to medial hypothalamus whose functions are mediated by GABAA receptors. When coupled with our previous findings, these results reveal the presence of reciprocal GABAergic inhibitory pathways between the medial and lateral hypothalamus. The findings suggest that functions associated with either the lateral or medial hypothalamus, but not both, can be activated at a given time.

Aggression↗
PubMed1992

[Amphetamine--induced rage reaction in mice and its mechanism].

Rage reaction was induced in mice by ip amphetamine sulfate (APT) 15 mg/kg. Mice appeared hyperreactive after 6 min and then squeaked and fought each other. These manifestations were most distinct in 15-30 min and subsided after 40-70 min. At 20 degrees C and 25 degrees C, the occurrence of rage reaction was 85.0% and 90.0% respectively. The ED50 of APT for eliciting rage reaction was 11.8 +/- 2.1 mg/kg ip. No significant difference in the induction of rage reaction was observed between male and female mice but ambient temperature affected the occurrence of this reaction. Neuroleptic drugs (chlorpromazine, haloperidol, tardan and clozapine), anxiolytic drugs (diazepam and meprobamate) and reserpine suppressed the rage reaction induced by APT in mice. Phenobarbital and pentobarbital (at sedative doses), atropine, scopolamine, phentolamine and propranolol exerted no influence on APT--induced rage reaction. Amantadine, levodopa and apomorphine at lower doses potentiated the rage inducing effect of APT. Moreover, at higher doses amantadine or levodopa alone also evoked rage reaction similar to that induced by APT. Therefore, it may be deduced that the APT-induced rage reaction results from increased release of dopamine in limbic system and has nothing to do with the simultaneous epinephrine release. The available data indicate that the APT--induced rage reaction in mice deserves to be recommended as an animal model for screening potential neuroleptic drugs. The merits and shortcomings of this new model are discussed.

Amphetamine↗